Essential role of p38 gamma in K-ras transformation independent of phosphorylation
Qi, X. M.
Han, J. H.
- 生命科学－已发表论文 
MAPK cascades play the critical role in regulating Ras oncogene activity by phosphorylation-dependent mechanisms. Whereas the ERK MAPK pathway is required for Ras transformation, our previous works established that the p38 activity is inhibitory to Ras signaling in both experimental and ras-mutated cancer cells ( Chen, G., Hitomi, M., Han, J., and Stacey, D. W. ( 2000) J. Biol. Chem. 275, 38973 - 38980; Qi, X., Tang, J., Pramanik, R., Schultz, R. M., Shirasawa, S., Sasazuki, T., Han, J., and Chen, G. ( 2004) J. Biol. Chem., 279, 22138 - 22144). Here we report that K-Ras activated p38 gamma, a p38 MAPK family member, by inducing its expression without increasing its phosphorylation and that depletion of induced p38 gamma suppressed Ras transformation in rat intestinal epithelial cells. This p38 gamma activity contrasts with that of its family member, p38 gamma, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. Mechanistic analyses showed that unphosphorylated p38 gamma may promote Ras transformation through an increased complex formation with ERK proteins. Significantly, functional p38 gamma protein was expressed only in K-ras-mutated human colon cancer cells, and p38 gamma transcripts were ubiquitously increased in a set of primary human colon cancer tissues. These studies thus demonstrate the essential role of p38 gamma in K-Ras transformation independent of phosphorylation, and elevated p38 gamma may serve as a novel diagnostic marker and therapeutic target for human colon cancer.